title: Increased soluble urokinase plasminogen activator receptor (suPAR) is associated with thrombosis and inhibition of plasmin generation in paroxysmal nocturnal hemoglobinuria (PNH) patients.
abstract: Paroxysmal nocturnal hemoglobinuria (PNH) is an acquired genetic disorder of the bone marrow that produces intravascular hemolysis, proclivity to venous thrombosis, and hematopoietic failure. Mutation in the PIG-A gene of a hematopoietic stem cell abrogates synthesis of glycosylphosphoinositol (GPI) anchors and expression of all GPI-anchored proteins on the surface of progeny erythrocytes, leukocytes, and platelets. Urokinase plasminogen activator receptor (uPAR), a GPI-linked protein expressed on neutrophils, mediates endogenous thrombolysis through a urokinase-dependent mechanism. Here we show that membrane GPI-anchored uPAR is decreased or absent on granulocytes and platelets of patients with PNH, while soluble uPAR (suPAR) levels are increased in patients' plasma. Serum suPAR concentrations correlated with the number of GPI-negative neutrophils and were highest in patients who later develop thrombosis. In vitro, suPAR is released from PNH hematopoietic cells and from platelets upon activation, suggesting that these cells are the probable source of plasma suPAR in the absence of GPI anchor synthesis and trafficking of uPAR to the cell membrane. In vitro, the addition of recombinant suPAR results in a dose-dependent decrease in the activity of single-chain urokinase. We hypothesized that suPAR, prevents the interaction of urokinase with membrane-anchored uPAR on residual normal cells.
authors.affiliation: National Heart Lung and Blood Institute, Hematology Branch, Office of Biostatistics Research, Division of Prevention and Population Sciences, National Institutes of Health, Bethesda, MD 20892-1260, USA. Sloande@nhlbi.nih.gov
authors.forename: Elaine M
authors.initials: EM
authors.lastname: Sloand
authors.forename: Loretta
authors.initials: L
authors.lastname: Pfannes
authors.forename: Phillip
authors.initials: P
authors.lastname: Scheinberg
authors.forename: Kenneth
authors.initials: K
authors.lastname: More
authors.forename: Colin O
authors.initials: CO
authors.lastname: Wu
authors.forename: McDonald
authors.initials: M
authors.lastname: Horne
authors.forename: Neal S
authors.initials: NS
authors.lastname: Young
mesh_terms: D001773:Blood Cells / Q000378:metabolism; D005260:Female; D005341:Fibrinolysin / Q000032:analysis*; D005786:Gene Expression Regulation / Q000235:genetics; D006410:Hematopoiesis / Q000235:genetics; D006412:Hematopoietic Stem Cells / Q000378:metabolism*; D006457:Hemoglobinuria, Paroxysmal / Q000097:blood* / Q000150:complications / Q000235:genetics; D006461:Hemolysis / Q000235:genetics; D006801:Humans; D008297:Male; D008565:Membrane Proteins / Q000235:genetics / Q000378:metabolism; D009154:Mutation; D021381:Protein Transport / Q000235:genetics; D055293:Receptors, Urokinase Plasminogen Activator / Q000097:blood* / Q000235:genetics; D012995:Solubility; D013927:Thrombosis / Q000097:blood* / Q000209:etiology / Q000235:genetics; D014568:Urokinase-Type Plasminogen Activator / Q000097:blood* / Q000235:genetics
chemical_list: D008565:Membrane Proteins; C524898:PLAUR protein, human; D055293:Receptors, Urokinase Plasminogen Activator; C080086:phosphatidylinositol glycan-class A protein; D005341:Fibrinolysin; D014568:Urokinase-Type Plasminogen Activator